Targeting thyroid hormone receptors with TH analogs

TOPIC: A novel thyroid hormone analog with potential clinical use

Title: Single-dose targeting of thyroid hormone receptor- agonists to the liver reduces cholesterol and triglycerides and improves the therapeutic index.

Authors: Erion MD, Cable EE, Ito BR, Jiang H, Fujitaki JM, Finn PD, Zhang B-H, Hou J, Boyer SH, van Poelje PD, & Linemeyer DL.

Reference: Proceedings of the National Academy of Sciences 104: 15489-15495, 2007



Thyroid hormone (TH) agonists can potentially be used to lower cholesterol and treat obesity. However, most agonists are limited by their dose-limiting side effects on heart, muscle, bone, and the thyroid hormone axis (THA).


The authors have developed a p450-activated -prodrug- (MB-07811) that is metabolized to a potent thyroid hormone analog (MB-07834) when extracted by the liver on first pass, and excreted in the bile. The effects of MB-07811 on cholesterol, triglycerides, body weight and THA were examined and compared with T 3 and another TH analog (KB-141) that has more general, rather liver-specific, effects.

Design: Studies were performed in cholesterol-fed rats and diet-induced obese (DIO) mice to test the efficacy of MB-07811, T 3 , and KB-141 on heart rate and liver function. Left ventricular function, THA, cholesterol, triglycerides, glucose, body weight, and thyroid hormone levels were measured and compared. Pharmokinetic studies on cultured rat hepatocytes and normal rats were also performed.


Rats and mice were treated with various doses of these drugs for various time ranges between 3 hours and 14 days.


MB-07811, a cytochrome P450-activated -prodrug- of a phosphonate-containing TR agonist exhibits increased TR activation in the liver relative to extrahepatic tissues and an improved therapeutic index. Pharmacokinetic studies in rats demonstrated that the prodrug (2R,4S)-4-(3-chlorophenyl)-2-[(3,5-dimethyl-4-(4'-hydroxy-3'- isopropylbenzyl)phenoxy)me-thyl]-2-oxido-[1,3,2]-dioxaphosphonane (MB-07811) undergoes first-pass hepatic extraction and that cleavage of the prodrug generates the negatively charged TR agonist (3,5-dimethyl-4-(4'-hydroxy-3'-isopropylbenzyl)phenoxy)methylphosphonic acid (MB-07344), which distri-butes poorly into most tissues and is rapidly eliminated in the bile. Enhanced liver targeting was further demonstrated by comparing the effects of MB-07811 with T 3 and a non-liver-targeted TR agonist, 3,5-dichloro-4-(4-hydroxy-3-isopropylphenoxy)phenylacetic acid (KB-141) on the expression of TR agonist-responsive genes in the liver and six extrahepatic tissues. The pharmacologic effects of liver targeting were evident in the normal rat, where MB-07811 exhibited increased cardiac sparing, and in the diet-induced obese mouse, where, unlike KB-141, MB-07811 reduced cholesterol and both serum and hepatic triglycerides at doses devoid of effects on body weight, glycemia, and the THA.


These results indicate that targeting TR agonists to the liver has the potential to lower both cholesterol and triglyceride levels with an acceptable safety profile.


This manuscript by Erion et al. describes a thyroid hormone (TH) agonist, MB-07834, that specifically targets the liver due to p450 conversion from a prodrug, MB-07811. The former has a high therapeutic index with respect to cardiac parameters, glucose, body weight, and suppression of HPT axis while significantly decreasing serum cholesterol and triglyceride levels in rodents. This study thus describes a new class of selective TH agonists that utilize tissue-specific metabolism, and offer a novel approach to therapeutic usage of such TH agonists, in addition to other compounds that have been developed which have tissue-selective uptake or thyroid hormone receptor (TR) isoform-specificity.

This is a well-written and well-conducted study that describes a novel approach to designing drugs that have a tissue-specific effect. MB-07834 is rapidly cleared by liver and biliary system, and also has very little enterohepatic recirculation, all of which contribute to low systemic levels, when the prodrug MB-07811 is administered either intravenously or orally. The high therapeutic index suggest that MB-07811 or similar drugs that are selectively extracted, metabolized, and excreted by the liver may have utility as novel anti-cholesterol and anti-obesity agents. A similar strategy could be employed by other drugs that are metabolically activated by the liver. Summary and commentary prepared by Paul Yen (related to Chapter 3 of TDM)